Huntingdon's Disease

Question 1

what is huntingdon’s disease?

Answer 1

An autosomal dominant , hereditary neurodgenerative disease

Question 2

Does inheritance depend on gender?

Answer 2

no (independant of gender)

Question 3

what three things is HD characterised by?

Answer 3

• cognitive
• behavioural
• motor dysfunction

Question 4

when was HD recognised as a inherited disorder?

Answer 4

1872

Question 5

where is there a higher prevalence of HD?

Answer 5

America, Australia and most european and western countries

Question 6

where is there a lower prevalencec of HD?

Answer 6

Asia and Africa
Japan and China

Question 7

which chromosome is HD located on?

Answer 7

4

Question 8

what about the HTT gene causes the development of HD?

Answer 8

expansion of the gene

Question 9

What is the job of the HTT gene?

Answer 9

to pull in its glutamine tail

Question 10

how many repeats give rise to normal HTT function?

Answer 10

10 to 35 repeats

Question 11

how many repeats are associated with onset of HD?

Answer 11

36 repeats or more

Question 12

what is anticipation?

Answer 12

the earlier onset with each generation

Question 13

what is the three stages of clinical progression

Answer 13

Presymptomatic
Prodromal
Manifest

Question 14

What is stage 1 of clinical progression of HD?

Answer 14

Presymptomatic - you may carry an elevated number of copies but you haven’t manifested any symptoms

Question 15

what is stage 2 of clinical progression of HD?

Answer 15

Prodromal - when you’re already manifesting some symptoms and you may be picked up by a clinician or not

Question 16

what type of neuron does HD mainly affect?

Answer 16

Medium Spiny Neurons
makes up 95% of neurons

Question 17

what is the two main things mtHTT leads to (neurodegen)?

Answer 17

• dysregulated transcription
• impairment of proteostatis

Question 18

what three things can occur due to mtHTT’s effects?

Answer 18

• synaptic dysfunction
• mitochondrial toxicity and energy imbalance
• axonal transport impairment

Question 19

what are the two misfolding pathways that mtHTT can lead to ?

Answer 19

• LOF : sequestering proteins into aggregates away from where it acts, modifying protein interaction making them weaker so binding is lost
• GOF : expanding PolyQ creates protein conformers which are toxic and create new activity/ interactions

Question 20

how does mtHTT affect transcriptional machinery?

Answer 20

• inhibits 75% of transcription
• inhibits histone modifications, reducing transcription of genes (acetylation enzymes in particular)
• eg. inhibition of CREB dependant trancription

Question 21

what can LOF look like in mtHTT?

Answer 21

Anti-apoptotic activity lost
- HTT blocks procaspase-9 by direct binding but mtHTT has reduced procaspase-9 binding

Question 22

what can GOF look like in mtHTT?

Answer 22

• enhanced sensitivity of mPTP to Ca2+ - inducing pore opening and release of Cytc
• reduced membrane potential
• decreased Ca2+ buffering capacity
• Increased in ROS production

Question 23

Name two HTT approved drugs?

Answer 23

Tetrabenazine
Deutetrabenazine

Question 24

what are ASO (Antisense Oligonucleotides)?

Answer 24

Allele-selective drugs, that bind to and target for degradation, mtHTT mRNA via single nucleotide polymorphisms

Question 25

what four factors cause variability in disease progression?

Answer 25

1) CAG repeat length
2) Genetic Modifiers
3) Enviromental Factors
4) Epigenetic factors

Question 26

what is the mutation of HTT?

Answer 26

an abnormal expansion of a glutamine stretch (PolyQ) in its N-terminal sequence

Question 27

describe axons in mtHTT?

Answer 27

• transporter deficits
• transmitter release deficits
• Ca2+ homeostasis
• Proteosomal dysfunction
• signalling dysfunction

Question 28

describe Medium Spiny Neurons in HD?

Answer 28

• high level of glutamate cellular depolarisation (NMDA mediated Ca2+ influx)
• high firing rate and high metabolic demands
• long projection axon very dependant on efficient transport
• selective expression of neuropeptides and selective expression of Ca2+ binding proteins